Crotyl i-methyl-propyl thiobarbi



Patented Oct. 1, 1940 UNITED STATES CROTYL l-lVLETHYL-PROPYL THIOBARBI- TURIC COMPOUND, AND lVIETHOD OF PRO-- DUCING IT Horace A. Shonle and Wilbur J. Doran, Indianapolis, Ind., assignors to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Application August 12, 1939, Serial No. 289,900

3 Claims.

Our present invention is directed to a new anesthetic, sedative, and sleep-producing compound, crotyl l-methyl-propyl thiobarbituric acid, and its salts, and to the method of producing them.

Salts of this new crotyl l-methyl-propyl thiobarbituric acid are found to have surprising properties. On parenteral administration they are definitely sedative and anesthetic in their physiological action, and have definite analgesic properties. The minimum. anesthetic dose of the sodium salt, for instance, is unusually low; for that sodium salt is effective in doses of 25 to 30 mg. per kg. of body weight to produce a com: plete anesthesia in rabbits on intravenous administration. These salts have a high therapeutic ratio, higher than that of the salts of any other thiobarbituric acid which we have examined and tested; for the minimum lethal dose of the sodium salt on intravenous administration into rabbits is 60 mg. per kg. of body weight, which makes the unusually high therapeutic ratio (M. L. D. divided by M. A. D.) of 2.40. Their onset of action is rapid; the sodium salt usually takes effect in rabbits in less than a minute. Their duration of action is remarkably short; for a rabbit which has been put into complete anesthesia by the sodium salt ordinarily comes out of the anesthesia completely within thirty-five minutes. Further, on coming out of that anesthesia, the rabbit does not exhibit the period of muscular incoo'r'dination that is almost universally observed with known barbiturates. In addition, the anesthesia it produces is complete and quiet. This is most surprising in view of the fact that the sodium salt of the isomeric crotyl n-butyl thiobarbituric acid (which we have also prepared and tested) produces convulsions, without anesthesia at all, at any dose below the fatal dose; and that the othersynthesizable isomer, sodium crotyl 2-methylpropyl thiobarbiturate, (which we have also produced and tested and which, as the acid, has been named in the literature, in French Patent No. 813,700,) produces a very unquiet anesthesia that is accompanied by startling tremors, rendering it unfit for use as an anesthetic; while the remaining theoreticallypossible isomer, crotyl tertiary-butyl thiobarbituric acid, cannot be synthesized by any method of which we know.

Our new crotyl l-methyl-propyl thiobarbituric acid and its salts may berepresented by the following formula:

in which X represents a member of the class consisting of hydrogen (if the compound is an acid), and (if the compound is a salt).an alkali metal, such as sodium, an equivalent of an alkaline-earth metal, such as calcium, ammonium, mono-alkyl ammonium, such as -NI-I3CH3, dialkyl ammonium, such as NH2(C2I-I5)2, and alkanol ammonium, such as NH3CH2CH2OH.

In preparing our new crotyl l-methyl-propyl thiobarbituric acid, it is important that the crotyl halide (preferably bromide or chloride) used in preparing the crotyl l-methyl-propyl ethylmalonate or the crotyl l-methyl-propyl ethylcyanacetate from which the desired crotyl l-methyl-propyl thiobarbituric acid is obtained, be substantially free from any isomer, particularly from the l-methyl-allyl halide into which the crotyl halide partially isomerizes on standing to produce an equilibrium mixture. Therefore, it is important that there be a separation of such an equilibrium mixture of halides to obtain therefrom substantially isomer-free the desired crotyl halide (chloride or bromide) immediately before preparing the crotyl l-methylpropyl .ethylmalonate or ethylcyanacetate; which separation of isomers may be done by known methods. (See Winstein and Young, Jour. Am. Chem. Soc., vol. 58, page 104, 1936; Kharasch, Kritchevsky, and Mayo, Jour. Org. Chem, vol. 2, page 489, 19378.)

In preparing our desired crotyl l-methylpropyl thiobarbituric acid, we may proceed by either the malonic-ester method or the cyan acetic-ester method but we prefer the malonicester method. v

MaZom'c-ester method.

To make the disubstituted crotyl l-methylpropyl ethylmalonate, we condense acrotyl halide with l-methyl-propyl ethylmalonate, or a 1- methyl-propyl halide with mono-crotyl ethylmalonate, in the presence of sodium ethylate, in the manner customary for making disubstituted malonic esters.

EmampZe.-One mol. of sodium is dissolved in from lOto 12 times its weight of absolute alcohol, under a reflux condenser. One mol. of lmethyl-propyl ethylmalonate is then added. Part of the alcohol that was used may then be removed, as by vacuum distillation, and then about 1.1 mols. of crotyl bromide (or crotyl chloride) are gradually added. The'crotyl bromide (or crotyl chloride) used should be substantially isomer-free, as has already been pointed out. The mixture is refluxed for some hours, desirably until it no longer shows an alkaline reaction to moist litmus paper. Mose of the alcohol remaining, whether or not some had previously been removed, is now removed'by vacuum distillation, leaving an oily residue. Water is added to this residue to dissolve out the sodium bromide (or chloride) present in it; and the oily layer, which contains the desired crotyl 1- methyl-propyl ethylmalonate is separated and dried. This crude crotyl l-methyl-propyl ethylmalonate is purified by fractional distillation in vacuo; and when purified is found to boil at 118-123 C., uncorrected, at about 3 to 4 mm. pressure. It is a substantially colorless liquid, and is represented by the following formula:

orn-om-cn o 0-0 01m As has already been indicated, instead of using l-methyl-propyl ethylmalonate and crotyl bromide (or crotyl chloride) We may use mono-crotyl ethylmalonate and l-methyl-propyl bromide (or chloride). In that case, however, the crotyl ethylmalonate should be substantially isomerfree; for which purpose care should be taken in making it.

So far as we know, this crotyl ethylmalonate is a new substance. It is made by condensing 1 mol. of ethylmalonate with about 1.1 mols. of crotyl bromide (or chloride) in the presence of a solution of 1 mol. of sodium ethylate in absolute alcohol. The crotyl bromide (or chloride) should be substantially isomer-free. The mixture is refluxed for some hours, desirably until it no longer shows an alkaline reaction to moist litmus paper. The alcohol is now removed by vacuum distillation, leaving an oily residue. Water is added to this residue to dissolve out the sodium bromide (or chloride) present in it; and the oily layer, which contains the desired crotyl ethylmalonate, is separated and dried. The crude crotyl ethylmalonate is purified by fractional distillation in vacuo; and when purified is found to boil at about 121 C., at 13 mm. pressure. It is a substantially colorless liquid, and may be represented by the following formula:

CO-OC2H5 From the crotyl l-methyl-propyl ethylmalonate, prepared by either process outlined above, we may prepare crotyl l-methyl-propyl thiobarbituric acid as follows:

Three mols. of sodium are dissolved in 10 to 12 times its weight of absolute alcohol under a refiux condenser. To these are added about 1.6 mols. of thiourea and 1 mol. of crotyl l-methylpropyl ethylmalonate. The mixture is gently refluxed for about 15 to 20 hours, after which most of the alcohol is removed by vacuum distillation. The residue is dissolved in water, and a sufficient amount of dilute acid, such as hydrochloric acid, is added to completely throw out of solution the crotyl l-methyl-propyl thiobarbituric acid which has been formed. This crotyl l-methylpropyl thiobarbituric acid generally comes out of solution in the form of an oil which solidifies on standing. This solid so obtained is separated, as by filtration; is then dried, and may be washed with gasoline; and is then purified by recrystallization, as from dilute alcohol.

This crotyl l-methyl-propyl thiobarbituric acid is a whitish crystalline solid, with a slight yellow tinge; melts at about 134-136 0., corrected; is insoluble in water, and readily soluble in alcohol and in ether; and is bitter tasting. Its formula is:

CHa-CH=CHCH2 CH:CH2-(|3H Cycmacetic-ester method When ethylcyanacetate is used instead of ethylmalonate in the preparation of crotyl 1- methyl-propyl thiobarbituric acid, purified crotyl chloride (or bromide) may be reacted with 1- methyl-propyl ethylcyanacetate, or l-methylpropyl bromide may be reacted with crotyl ethylcyanacetate. In using the latter procedure 1 mol. of sodium is dissolved in 10 to 12 times its weight of absolute alcohol under a reflux condenser. 1 mol. of ethylcyanacetate is then added. The sodium ethylcyanacetate separates out as a solid at this stage. Then about 1.1 mols. of purified crotyl chloride (or bromide) are added and the mixture is refluxed for about 15 hours. The alcohol is removed by vacuum distillation, leaving an oily residue. Water is added to this residue to dissolve out the sodium chloride present in it; and the oily layer, which contains the desired crotyl ethylcyanacetate, is separated and dried. This crude crotyl ethylcyanacetate is purified by fractional distillation in vacuo, and when so purified is found to boil at 97-105 C., at about 5 mm. pressure. It is a substantially colorless liquid and is represented by the following formula:

H ON In a manner similar to the above procedure, crotyl l-methyl-propyl ethylcyanacetate may be prepared from secondary butyl bromide (or chloride) and crotyl ethylcyanacetate.

The crotyl l-methyl-propyl ethylcyanacetate may be purified by fractional distillation, and is found to boil at 118 to 119 C. at about 5 mm. pressure. It is a substantially colorless liquid, and is represented by the following formula:

From the disubstituted crotyl l-methyl-propyl ethyl-cyanacetate, prepared by either procedure, we may make crotyl l-methyl-propyl thiobarbituric acid, as follows:

3 mols. of sodium are dissolved in 10 to 12 times its weight of absolute alcohol under a reflux condenser. To these are added about 1.6 mols. of thiourea and 1 mol. of crotyl l-methyl-propyl cyanacetate. The mixture is gently refluxed for about 15 to 20 hours, after which most of the alcohol is removed by vacuum distillation. The residue is dissolved in Water, and sufiicient dilute acid, such as hydrochloric acid, is added to make the solution barely acid to litmus paper. Excess acid is undesirable, because it will dissolve the crotyl l-methyl-propyl imino thiobarbituric acid which has been formed; whereas if the solution is made just barely acid that crotyl l-methylpropyl imino thiobarbituric acid separates out as a solid. This solid so obtained is separated, as by filtration; is then dried, and is then purified by recrystallization, as from dilute alcohol.

This crotyl 1-methyl-propyl imino thiobarbituric acid is a whitish solid which melts at about 235-236 C., corrected, with foaming. It is represented by the following formula:

On boiling with aqueous hydrochloric acid or aqueous alcoholic hydrochloric acid, the crotyl l-methyl-propyl imino thiobarbituric acid is converted by hydrolysis into crotyl I-methyl-propyl thiobarbituric acid, which melts at 134-136" C.,

corrected.

Thiobarbiturates may readily be obtained from this crotyl l-methyl-propyl thiobarbituric acid. These thiobarbiturates are represented by Formula 1 above, with X representing an alkali metal, an equivalent of an alkaline-earth metal, ammonium, mono-alkyl ammonium, di-alkyl ammonium, or alkanol ammonium. These thiobarbiturates may be obtained by the reaction of the crotyl l-methyl-propyl thiobarbituric acid, in a suitable solvent, with either the hydroxide or the ethylate of the desired inorganic base, or with ammonia, or with the desired alkyl or alkanol amine. The sodium salt, for instance, is represented by the following formula:

CHz-OH=CHCH: (lo-NH (8) OHPCHir-CH The other alkali-metal salts have the same general formula, save for the substitution of the other metal for sodium. These salts are prepared in the general way of preparing alkalimetal salts from barbituric acids or thiobarbituric acids. The sodium salt is a whitish solid, with a slight yellow tinge, is soluble in water and alcohol, and is insoluble in ether. It is bittertasting, and its aqueous solution is alkaline in reaction.

When this sodium salt is desired in stable form sufficiently free from contaminants so that clear water solutions thereof suitable for intravenous injection may be obtained, it is produced by the method set forth in the Shonle Patent No. 1,856,- 792, granted May 3, 1932.

The ammonium and alkyl-amine and alkanolamine salts made of crotyl l-methyl-propyl thiobarbituric acid may be produced by the reaction of that acid with ammonia or .with the desired amine, in the usual manner of producing ammonium or alkyl-amine or alkanol-amine barbiturates and thiobarbiturates. The formula of this corresponds in general to Formula 1 above, save that NH4 or the proper substituted-ammonium radical is substituted for H at the point X of Formula 1.

We claim as our invention:

1. A crotyl l-methyl-propyl thiobarbituric compound which is represented by the following formula:

CHa-CEh-CH 3. Sodium crotyl l-methyl-propyl thiobarbiturate, which is represented by the following formula:

HORACE A. SHONLE. WILBUR J, DORAN. 

